Post-traumatic stress disorder (PTSD) exacts a steep toll on the well being of civilians and veterans alike. Alternatives to standard treatment are urgently needed. Typical PTSD therapy, e.g. long-term treatment with a serotonin-selective reuptake inhibitor (SSRI) coupled with psychotherapy, does help a significant number of patients, but it fails to treat the majority of PTSD sufferers. Recently, patients with treatment-resistant PTSD have achieved dramatic and durable remission of their symptoms with a surprising treatment, MDMA-assisted psychotherapy. The recreational drug MDMA, also known as ?ecstasy?, had been used as an aid to treat anxiety and PTSD prior to its illegalization in 1985. Recently approved clinical trials demonstrate that MDMA-assisted psychotherapy is safe and effective for PTSD. MDMA enhances feelings of trust, emotional openness and empathy, helping PTSD patients overcome obstacles to therapy, such as extreme anger, emotional numbing and overwhelming anxiety. This project aims to define the biology and the neurophysiology that create the prosocial effect of MDMA. By defining the mechanism for MDMA's prosocial, therapeutic effect we can begin creating new treatments that harness the same underlying biological processes. Improving the quality of social interaction has implications for many disorders where sociability is impaired, from autism to major depression. Remarkably, patients in preliminary clinical trials have experienced years-long remission of PTSD after a single dose of MDMA in the context of psychotherapy. Further, MDMA's therapeutic onset can be measured in minutes and hours rather than the weeks and months typical of SSRIs. MDMA's rapid onset and lasting therapeutic effect suggest that it is a powerful catalyst for behavioral recovery by means of therapeutic synaptic plasticity; an acute change in behavior reflects plasticity at the level of neural circuits, neurons, and synapses. This well-defined time window dramatically simplifies the search for an underlying neural mechanism of its prosocial effect. If we can measure MDMA's most salient therapeutic aspects on this short time scale, we can design experiments that explicitly test the requirements for its mechanism, using tools ideally suited to acute measurement and intervention. Recent studies of social reward and interaction in mice implicate serotonin and dopamine release in the nucleus accumbens (NAc), a brain area centrally involved in reward and social interaction. This project will systematically evaluate the role of each of these elements in MDMA's mechanism using behavioral pharmacology, brain region-specific drug injection, optogenetics, and imaging of neurons' activity during behavior. Finally this study will carry out a detailed examination of how MDMA produces both short- and long- term effects on synapses in the NAc.